摘要Viral co-infection has been found in animals;however,the mechanisms of co-infection are unclear.The abun-dance and diversity of viruses in water make fish highly susceptible to co-infection.Here,we reported a co-infection in fish,which resulted in reduced host lethality and illustrated the intracellular molecular mechanism of viral co-infection.The spring viremia of carp virus(SVCV)is a highly lethal virus that infects Cyprinidae,such as zebrafish.The mortality of SVCV infection was significantly reduced when co-infected with the grass carp reovirus(GCRV).The severity of tissue damage and viral proliferation of SVCV was also reduced in co-infection with GCRV.The transcriptome bioinformatics analysis demonstrated that the effect on the host transcripts in response to SVCV infection was significantly reduced in co-infection.After excluding the extracellular interactions of these two viruses,the intracellular mechanisms were studied.We found that the GCRV NS38 remarkably decreased SVCV infection and viral proliferation.The interaction between GCRV NS38 and SVCV nucleoprotein(N)and phosphoprotein(P)proteins was identified,and NS38 downregulated both N and P proteins.Further analysis demonstrated that the N protein was degraded by NS38 indispensable of the autophagy receptor,sequestosome 1(p62).Meanwhile,K63-linked ubiquitination of the P protein was reduced by NS38,leading to ubiquitinated degradation of the P protein.These results reveal that the intracellular viral protein interactions are a crucial mechanism of co-infection and influence the host pathology and expand our understanding in intra-cellular viral interactions co-infection.